Drosophila Snazarus Regulates a Lipid Droplet Population at Plasma Membrane-Droplet Contacts in Adipocytes

Ugrankar, Rupali; Bowerman, Jade; Hariri, Hanaa; Chandra, Mintu; Chen, Kai‐En; Bossanyi, Marie-France; Datta, Sudarshana; Rogers, Sean; Eckert, Kaitlyn M.; Vale, Gonçalo; Victoria, Alexia; Fresquez, Joseph; McDonald, Jeffrey G.; Jean, Steve; Collins, Brett M.; Henne, W. Mike

doi:10.1016/j.devcel.2019.07.021

Cited by 83 publications

(143 citation statements)

References 49 publications

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“…On the other hand, when excessive fat accumulates in the cytosol, it impairs mitochondrial function, often leading to decreased mitochondrial fatty acid oxidation which in turn worsens the obesity 49 . Obesity also induces ER stress, which could impair normal lipid synthesis and trafficking, since ER is the site of lipid synthesis and trafficking 50‐52 . Therefore, mitochondrial metabolism can be the cause or the result of abnormal adipogenesis in different contexts.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial aconitase controls adipogenesis through mediation of cellular ATP production

et al. 2020

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Mitochondrial aconitase (Aco2) catalyzes the conversion of citrate to isocitrate in the TCA cycle, which produces NADH and FADH2, driving synthesis of ATP through OXPHOS. In this study, to explore the relationship between adipogenesis and mitochondrial energy metabolism, we hypothesize that Aco2 may play a key role in the lipid synthesis. Here, we show that overexpression of Aco2 in 3T3-L1 cells significantly increased lipogenesis and adipogenesis, accompanied by elevated mitochondrial biogenesis and ATP production. However, when ATP is depleted by rotenone, an inhibitor of the respiratory chain, the promotive role of Aco2 in adipogenesis is abolished. In contrast to Aco2 overexpression, deficiency of Aco2 markedly reduced lipogenesis and adipogenesis, along with the decreased mitochondrial biogenesis and ATP production. Supplementation of isocitrate efficiently rescued the inhibitory effect of Aco2 deficiency. Similarly, the restorative effect of isocitrate was abolished in the presence of rotenone. Together, these results show that Aco2 sustains normal adipogenesis through mediating ATP production, revealing a potential mechanistic link between TCA cycle enzyme and lipid synthesis. Our work suggest that regulation of adipose tissue mitochondria function may be a potential way for combating abnormal adipogenesis related diseases such as obesity and lipodystrophy. K E Y W O R D S cell differentiation, mitochondrial metabolism, TCA cycle | 6689 CHEN Et al.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial aconitase controls adipogenesis through mediation of cellular ATP production

et al. 2020

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“…The results for both species therefore contrast markedly with each other but also differ significantly from the clinical findings reported in both humans and dogs (1, 2, 15) ( Table 1). In this respect, zebrafish resemble, mutant Drosophila with a genetic ablation of snz, the homolog of snx14, which are also viable and survive into adulthood (14). This interspecies variation is evident despite evidence that SNX14 has a conserved biochemical role in lipid biogenesis across species from humans to yeast (Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…SNX14 has previously been associated with a role in endocytic/lysosomal/endoplasmic reticulum associated processes (1, 2, 9, 10) and mutations result in disruption to normal lipid metabolism (9,10). Interestingly, both SNX13 and SNX14 are homologues of the single Drosophila gene snz and the yeast gene Mdm1, both of which have also been demonstrated to have a role in lipid metabolism in Drosophila (11,14) and yeast (12) respectively. Additionally, human SNX13 mutations have also been implicated in disrupted lipid metabolism as evidenced by their association with lipid levels in serum (32,33).…”

Section: Discussionmentioning

confidence: 99%

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Diverse Species-Specific Phenotypic Consequences of Loss of Function Sorting Nexin 14 Mutations

Bryant¹,

Seda²,

Peskett³

et al. 2019

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Mutations in the SNX14 gene cause spinocerebellar ataxia, autosomal recessive 20 (SCAR20) in both humans and dogs. SCAR20 is understood to involve subcellular disruption to autophagy and lipid metabolism. Previously reported studies on the phenotypic consequences of SNX14 mutations have been limited to in vitro investigation of patient-derived dermal fibroblasts, laboratory engineered cell lines and developmental analysis of zebrafish morphants. In addition, studies have investigated the biochemical roles of SNX14 homologues Snz (Drosophila) andMdm1 (yeast) which have demonstrated an important role during lipid biogenesis.This study investigates the impact of constitutive Snx14 mutations in laboratory species: mice and zebrafish. Loss of SNX14 in mice was found to be embryonic lethal around mid-gestation. This is due to placental pathology that involves severe disruption to syncytiotrophoblast cell differentiation. Zebrafish carrying a homozygous, maternal zygotic snx14 genetic loss-of-function mutation contrasts with other vertebrates, being both viable and anatomically normal. Whilst no obvious behavioural effects were observed, elevated levels of neutral lipids and phospholipids resemble previously reported effects on lipid homeostasis in other species. The biochemical role of SNX14 therefore appears largely conserved through evolution while the overall consequences of loss of function varies considerably between species. New mouse and zebrafish models therefore provide valuable insights into the functional importance of SNX14 with distinct opportunities for investigating its cellular and metabolic function in vivo.

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“…Fat bodies have 2 populations of lipid droplets with distinct regulatory networks; surface lipid trafficking dependent or centrally localized large internally generated lipid droplets, of which spectrin is involved in regulating the surface lipid trafficking-generated droplet pools 28,42 . To determine if spectrin is altered in CR45362 fat bodies we immuno-stained for α and β Spectin (Fig 6B-E) in adults.…”

Section: Alpha Spectrin Rnai Leads To Nuclear Bundling Defectmentioning

confidence: 99%

Long non-coding RNA regulation of spermatogenesis and endosomal processes via the spectrin cytoskeleton inDrosophila

Bouska

Bai

2020

Preprint

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The spectrin cytoskeleton has been shown to be critical in diverse processes such as axon development and degeneration, myoblast fusion, and spermatogenesis. Spectrin can be modulated in a tissue specific manner through junctional protein complexes, however, it has not been shown that lncRNAs interact with and regulate spectrin. Here we provide evidence of a lncRNA that interacts with α and β Spectrin to regulate spermatogenesis and endosomal related activity in fat bodies of Drosophila. Protein-RNA and Protein-Protein biochemical analysis indicated the interaction between α and β Spectrin is modulated by the lncRNA CR45362. Immunocytochemistry revealed CR45362 is highly expressed in the basal testis while α and β Spectrin are clearly disrupted in this same region of CR45362 mutants. We genetically demonstrate α-Spectrin and CR45362 deficiencies cause spermatid nuclear bundling defects with congruous changes of spectrin distribution and reduced Lysotracker staining in the fat body. Our data suggests lncRNA regulation of spectrin could provide cells with a repertoire of modulatory molecules to manipulate cell-type specific cytoskeletal and endosomal requirements.

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Drosophila Snazarus Regulates a Lipid Droplet Population at Plasma Membrane-Droplet Contacts in Adipocytes

Cited by 83 publications

References 49 publications

Mitochondrial aconitase controls adipogenesis through mediation of cellular ATP production

Mitochondrial aconitase controls adipogenesis through mediation of cellular ATP production

Diverse Species-Specific Phenotypic Consequences of Loss of Function Sorting Nexin 14 Mutations

Long non-coding RNA regulation of spermatogenesis and endosomal processes via the spectrin cytoskeleton inDrosophila

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